A versatile approach for the asymmetric syntheses of (1R,9aR)-epiquinamide and (1R,9aR)-homopumiliotoxin 223G

Article abstract of DOI:10.1021/ol0602203

Using 5b as a common intermediate, the first asymmetric synthesis of (-)-epiquinamide (4) and a formal asymmetric synthesis of (-)-homopumiliotoxin 223G (2) is described. A key feature of our approach is the flexible introduction of a functionalized C

Full text of DOI:10.1021/ol0602203

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1435-1438
A Versatile Approach for the
Asymmetric Syntheses of
(1R,9aR)-Epiquinamide and
(1R,9aR)-Homopumiliotoxin 223G
Pei-Qiang Huang,* Zheng-Qing Guo, and Yuan-Ping Ruan
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian
ProVince, College of Chemistry and Chemical Engineering, Xiamen UniVersity,
Xiamen, Fujian 361005, P. R. China
pqhuang@xmu.edu.cn
Received January 25, 2006
ABSTRACT
Using 5b as
a
common intermediate, the first asymmetric synthesis of
(
−)-epiquinamide (4) and
a
formal asymmetric synthesis of
(
−)-homopumiliotoxin 223G (2) is described. A key feature of our approach is the flexible introduction of a functionalized C4 side chain to
(S)-3-benzyloxyglutarimide 7 in a regio- and diastereoselective manner. Utilization of a tandem Swern oxidation Grignard addition strategy
−
efficiently prevented racemization. An unexpected NaN3-promoted methanesulfonic acid elimination yielded 17, a reaction which could be
useful for the syntheses of 8-dehydrodesmethylpumiliotoxins such as alkaloid 235C (3).
Amphibian skin has been proven a rich source of bioactive
alkaloids, from which more than 800 alkaloids have been
detected.1 While pumiliotoxins 1 have been known since
1967,2 homopumiliotoxins such as (+)-homopumiliotoxin
223G (2) (Figure 1) were isolated 20 years later from the
Panamanian poison frog Dendrobates pumilio.3 The absolute
configuration of homopumiliotoxin 223G was determined
by asymmetric synthesis in 2000.4 Alkaloid 235C (3)1,5a and
three other indolizidine alkaloids were isolated from man-
tellid frogs.5b Their structures were revised recently to
8-dehydrodesmethylpumiliotoxins.1,5a,c In 2003, epiquinamide
(4), another unprecedented quinolizidine alkaloid, was
isolated in minute amounts (240 µg from 183 frogs) from
(4) (a) Kibayashi, C.; Aoyagi, S.; Wang, T. C.; Saito, K.; Daly, J. W.;
Spande, T. F. J. Nat. Prod. 2000, 63, 1157-1159. For an earlier asymmetric
synthesis of (+)-homopumiliotoxin 223G, see: (b) Aoyagi, S.; Hasegawa,
Y.; Hirashima, S.; Kibayashi, C. Tetrahedron Lett. 1998, 39, 2149-2152.
(5) (a) Andriamaharavo, N. R.; Andriantsiferana, M.; Stevenson, P. A.;
O′Mahony, G.; Yeh, H. J. C.; Kaneko, T.; Garraffo, H. M.; Spande, T. F.;
Daly, J. W. J. Nat. Prod. 2005, 68, 1743-1748. For original isolation and
initial structural determination, see: (b) Garraffo, H. M.; Caceres, J.; Daly,
J. W.; Spande, T. F.; Andriamaharavo, N. R.; Andriantsiferana, M. J. Nat.
Prod. 1993, 56, 1016-1038. For a racemic synthesis of the initially proposed
structure of alkaloid 235C, see: (c) Armstrong, P.; Feutren, S.; McAlonan,
H.; O′Mahony, G.; Stevenson, P. J. Tetrahedron Lett. 2004, 45, 1627-
1630.
(1) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68,
1556-1575.
(2) Daly, J. W.; Myers, C. W. Science 1967, 156, 970-973.
(3) (a) Tokuyama, T.; Nishimori, N.; Shimada, A.; Edwards, M. W.;
Daly, J. W. Tetrahedron 1987, 43, 643-652. (b) Garraffo, H. M.; Caceres,
J.; Daly, J. W.; Spande, Tf.; Andriamaharavo, Nr.; Andriantsiferana, M. J.
Nat. Prod. 1993, 56, 1016-1038. (c) Garraffo, H. M.; Spande, T. F.; Daly,
J. W.; Baldessari, A.; Gros, E. G. J. Nat. Prod. 1993, 56, 357-373.
10.1021/ol0602203 CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/07/2006

Figure 2. Retrosynthetic analysis.
Figure 1. Structures of some poison frog alkaloids.
envisioned that 5a/5b9c,12 could serve as the common
intermediates for 4 and 6a/6b (Figure 2). Lactams 5a/5b were
considered best synthesized by the stepwise reductive alky-
lation of 3-benzyloxyglutarimide 710 using either a C3 or C4
bifunctional chain 8a or 8b.
With these considerations in mind, our syntheses com-
menced with the reaction of (S)-3-benzyloxy-1-(4-methoxy-
benzyl) glutarimide10 7 with Grignard reagent 8b, easily
prepared from 1,4-butanediol. The Grignard reaction (CH2-
Cl2, -78 °C) proceeded smoothly to give a separable
diastereomeric mixture of 9 and the ring-opening keto-amide
tautomer 10 in a combined yield of 93% (Scheme 1). Since
the Ecuadorian poison frog Epipedobates tricolor.6 Epiquina-
mide represents a new structural class of nicotinic agonists
and potential lead compounds for the development of new
therapeutics and pharmacological probes for nicotinic recep-
tors. Although the relative stereochemistry of (+)-epiquina-
mide (4) has been confirmed by the first asymmetric
synthesis,7 its absolute configuration and further bioactivities
remain unknown due to the scarcity of epiquinamide from
natural sources.
The structural diversity and remarkable bioactivities
exhibited by these alkaloids have attracted much attention,
and a number of synthetic approaches have been reported.8
However, unlike pumiliotoxins, only two asymmetric syn-
theses of homopumiliotoxin 223G (2)4,9 and one asymmetric
synthesis of (+)-epiquinamide (4)7 have been disclosed. In
continuation of our studies on the use of protected 3-hy-
droxyglutarimide as a versatile building block for the
asymmetric syntheses of 3-piperidinols,10 we wished to
develop a unified strategy for the asymmetric syntheses of
(-)-epiquinamide and (-)-homopumiliotoxin 223G starting
from easily available (S)-3-benzyloxyglutarimide 7.
In view of the successful use of 6a11 and 6b9 as key
intermediates in the syntheses of pumiliotoxins 1 and
homopumiliotoxin 223G (2), respectively, 6b was selected
as our target en route to homopumiliotoxin 223G. It was
Scheme 1. Synthesis of 2-Piperidinone Alcohol 11
(6) Fitch, R. W.; Garraffo, H. M.; Spande, T. F.; Yeh, H. J. C.; Daly, J.
W. J. Nat. Prod. 2003, 66, 1345-1350.
(7) Wijdeven, M. A.; Botman, P. M. M.; Wijtmans, R.; Schoemaker, H.
E.; Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett. 2005, 7, 4005-4007.
(8) For a review on the syntheses of pumiliotoxins, see: Franklin, A.
S.; Overman, L. E. Chem. ReV. 1996, 96, 505-522.
(9) For a racemic synthesis of homopumiliotoxin 223G, see: (a) Santos,
L. S.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 6999-7001. For a formal
asymmetric synthesis, see: (b) Wang, B.; Fang, K.; Lin, G. Q. Tetrahedron
Lett. 2003, 44, 7981-7984. For a formal racemic synthesis, see: (c) Chen,
B. F.; Tasi, M. R.; Yang, C. Y.; Chang, J. K.; Chang, N. C. Tetrahedron
2004, 60, 10223-10231.
only the C-2 regioisomers could be isolated, the C-2
regioselectivity was higher than 95%. Being interconvertible
via the intermediacy of an N-acyliminium ion,10,13 the
diastereomeric and tautomeric mixture (9/10) was used in
the subsequent step without further separation. Thus, treat-
ment of the mixture of 9/10 with Et3SiH/BF3‚OEt2 (CH2Cl2,
(10) (a) Huang, P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett.
2003, 5, 1927-1929. (b) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett
2003, 1663-1667. (c) Liu, L.-X.; Ruan, Y.-P.; Guo, Z.-Q.; Huang, P.-Q.
J. Org. Chem. 2004, 69, 6001-6009. (d) Ruan, Y.-P.; Wei, B.-G.; Xu,
X.-Q.; Liu, G.; Yu, D.-S.; Liu, L.-X.; Huang, P.-Q. Chirality 2005, 17,
595-599. (e) Wei, B.-G.; Chen, J.; Huang, P.-Q. Tetrahedron 2006, 62,
190-198.
(12) D’Oca, M. G. M.; Pilli, R. A.; Vencato, I. Tetrahedron Lett. 2000,
41, 9709-9712.
(13) For recent reviews on the chemistry of N-acyliminium ion, see:
Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817-3856.
(11) Fox, D. N. A.; Lathburay, D.; Mahon, M. F.; Molloy, K. C.;
Gallagher, T. J. Am. Chem. Soc. 1991, 113, 2652-2656.
1436
Org. Lett., Vol. 8, No. 7, 2006

-78 °C to rt) provided, in one pot, the desilylated14 6-(4-
hydroxybutyl)-5-benzyloxy-2-piperidinone 11 in 60% yields.
The trans/cis diastereoselectivity was 96:4 as determined by
500 MHz 1H NMR spectroscopy. The stereochemistry of the
major diastereomer 11 was assumed to be trans in the light
of our previous results10 but was confirmed by its conversion
into (-)-epiquinamide (4)6,7 and the known lactam 6b.9
Tosylation of 11 led to 12 (92% yield), which after
oxidative N-deprotection using ceric ammonium nitrate in a
mixed MeCN-H2O (9: 1, v/v) solvent system provided 13
in 60-70% yields (Scheme 2). Treatment of 13 with sodium
epiquinamide (4) in 78% yield [mp 122-123 °C (lit.7 mp
124 °C); [R]20D -25.0 (c 0.26, CHCl3) [lit.7 [R]20D +28.0 (c
0.23, CHCl3) for the antipode]]. The physical data of the
synthetic molecule were identical with those reported.6,7
In the course of our investigation on the azidation of 15,
DMSO was selected as a solvent due to its improved ability
to dissolve sodium azide. Although treatment of 15 with
sodium azide in DMSO at 50-60 °C for 48 h gave 16 in
only 20% yield along with a large amount of the recovered
starting material, the reaction at higher temperature (70-75
°C) for 40 h led to eliminated product 1715 in 80% yield as
a single product (Scheme 4). Since the ring size of the fused
Scheme 2. Synthesis of the Common Intermediate 5b
Scheme 4. Preparation of the Eliminated Product 17
piperidine ring in 17 can be modified by using an appropriate
alkylating agent (e.g., 8a), this method could be useful for
the preparation of 8-dehydrodesmethylpumiliotoxins such as
alkaloid 235C (3).5
In pursuit of the synthesis of 6b, 5b was subjected to
Swern oxidation16 [(COCl)2, DMSO, CH2Cl2, -78 °C; -40
°C, i-Pr2NEt] (Scheme 5). To prevent possible racemization,
hydride afforded 14 in quantitative yield. Catalytic hydro-
genation (10% Pd/C, H2, 1 atm) of 14 gave the key
intermediate 5b in a yield of 98%.
For the synthesis of (1R,10R)-epiquinamide (4), 5b was
mesylated to give 15 (100% yield). The subsequent SN2
reaction with sodium azide yielded, besides the desired azide
16 (yield: 53%), an elimination product 1715 in 30% yield
(Scheme 3). Lithium aluminum hydride reductions of both
Scheme 5. A Formal Asymmetric Synthesis of
(-)-Homopumiliotoxin 223G (2)
Scheme 3. Synthesis of (-)-Epiquinamide
Hu¨nig base17 was used, and the reaction was quenched with
a NaOAc-HOAc buffer solution. In such a way, the desired
ketone 18 was isolated in 87% yield. Treatment of 18 with
methylmagnesium iodide afforded the known 6b9 as the sole
1
diastereomer (yield: 65%). The H and 13C NMR spectral
data of 6b were identical with those reported.9c The stereo-
selectivity of the reaction can be attributed to the addition
of methylmagnesium iodide from the less hindered face
opposite to the piperidine ring. Unfortunately, the ee of 6b
was only 6% as indicated by HPLC analysis on a chiral
the azide and the amide functional groups followed by
N-acetylation then provided the desired (1R,10R)-(-)-
(14) For a review on Et3SiH-mediated ionic hydrogenation, see: Kur-
sanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633-651.
(15) Lim, S. H.; Ma, S.; Beak, P. J. Org. Chem. 2001, 66, 9056-9062.
(16) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480-2482.
(17) Calvez, O.; Langlois, N. Tetrahedron Lett. 1999, 40, 7099-7100.
Org. Lett., Vol. 8, No. 7, 2006
1437

column. To overcome the problem of racemization, we tried
to perform the Grignard reagent addition with crude ketone
18; the ee of 6b was also disappointing (9%). On the other
hand, using MeTiCl318 as the methylating agent led to 6b in
only 33% yield. Finally, we elected to explore a one-pot
tandem Swern oxidation-methylmagnesium iodide addition
reaction.19 Gratifyingly, a 50% yield of 6b with 90% ee was
obtained from 5b. Since racemic 6b has been converted to
racemic homopumiliotoxin 223G (2),9a our synthesis of 6b,
together with that of Pilli,9a thus constitutes a formal
asymmetric synthesis of (-)-homopumiliotoxin 223G (2).
It is noteworthy that the present synthesis of 6b also
confirmed the trans-stereoselection in both the reductive
4-benzyloxybutylation of 7 and the nucleophilic addition to
18.
achieved in a total yield of 14.6%. The versatility of our
method was demonstrated by the synthesis of 6b, which
constituted a formal synthesis of homopumiliotoxin 223G
(-)-2. The easy accessibility to compound 17, by an
unexpected finding, in combination with the flexibility in
the reductive alkylation of 7 also formed the basis of
asymmetric syntheses of 8-dehydrodesmethylpumiliotoxins
such as alkaloid 235C. Application of the present strategy
to the asymmetric syntheses of other members of homopu-
miliotoxins and pumiliotoxins is in progress.
Acknowledgment. We are grateful to the NSF of China
(20390050, 20572088), the Ministry of Education (Key
Project 104201), and the NSF of Fujian Province (China)
(C0510001) for financial support.
In summary, starting from easily available glutarimide 7,
a concise, 10-step synthesis of (-)-epiquinamide (4) has been
Supporting Information Available: Experimental pro-
1
cedures and spectral data for all new compounds. H NMR
spectra of 4, 5b, 6b, 16, and 17; 13C NMR spectrum of 5b
and 16. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Reetz, M. T.; Kesseler, K.; Schmidtberger, S.; Wenderoth, B.;
Steinbach, R. Angew. Chem., Int. Ed. Engl. 1983, 22, 989-990.
(19) For other examples of one-pot Swern oxidation-Grignard reagents
addition, see: (a) Nubbemeyer, U. J. Org. Chem. 1996, 61, 3677-3686.
(b) Kubo, H.; Ishii, K.; Koshino, H.; Toubetto, K.; Naruchi, K.; Yamasaki,
R. Eur. J. Org. Chem. 2004, 1202-1213.
OL0602203
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